Post operative graft rejections are a major complication affecting the success of bone marrow and organ transplantations. However, through the use of immunosuppressive drug therapy, graft rejection in organ transplantation can be significantly reduced.
A wide variety of diseases can be characterized as "autoimmune diseases". Such diseases are similar to graft rejection, except that the rejection is of self tissue. Immunosuppressive therapy can also be of use in preventing this inappropriate self rejection.
One widely accepted immunosuppressant for the prevention of graft rejection is cyclosporin A (CsA). It is a natural product of fungal metabolism and has been demonstrated to have potent immunosuppressive activity in clinical organ transplantations. Calne, R. Y. et al., Br. Med. J. 282:934-936 (1981); White, D. J. C. Drugs 24:322-334 (1982). Although CsA is widely used in immunosuppressant therapy, its usage (particularly in high dosage) is often accompanied by side effects which include nephrotoxicity, hepatotoxicity and other central nervous system disorders.
The following diseases have been treated with cyclosporin A with positive results, confirming the importance of the autoimmune component in these diseases and their effective treatment with compounds working by selective T-cell immune suppression similar to cyclosporin A.
1) Ophthalmology: Uveitis, Behcet's disease and Grave's ophthalmopathy. PA0 2) Dermatology: Various autoimmune skin diseases including psoriasis. PA0 3) Hematology: Various diseases including anemia. PA0 4) Gastroenterology/Mepatology: Primary cirrhosis, autoimmune hepatitis, ulcerative colitis, Crohn's disease and other gastrointestinal autoimmune diseases. PA0 5) Neurology: Amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease"), myasthenia gravis and multiple sclerosis. PA0 6) Nephrotic Syndrome: Nephrotic syndrome, membranoproliferattve glomerulonephritis (MPGN) and related diseases. PA0 7) Rheumatoid Arthritis (RA) PA0 8) Insulin-Dependent Diabetes Mellitus (IDDM)
Weetman, A. P. et al., Lancet 486-489 (1982). Grave's ophthalmopathy. PA1 Nussenblatt, R. B. et al., Lancet 235-238 (1983). Uveitis. PA1 French-Constant, C. et al., Lancet 454 (1983). Behcet's disease. PA1 Sanders, M. et al., Lancet 454-455 (1983). Behcet's disease. PA1 Note: Cyclosporin A is currently approved in Japan for the treatment of Behcet's disease, the first autoimmune disease indication for this compound. PA1 Zabel, P. et al., Lancet 343 (1984). Acute dermatomyositis. PA1 van Joost, T. et al., Arch. Dermatol. 123:166-167 (1987). Atopic skin disease. PA1 Appleboom, T. et al., Amer. J. Med. 82:866-867 (1987). Scleroderma. PA1 Logan, R. A. and R. D. R. Camo, J. Roy. Soc. Med. 81:417-418 (1988). Eczema. PA1 Griffiths, C. E. M. et al., Brit. Med. J. 293:731-732 (1986). Psoriasis. PA1 Ellis, C. N. et al., J. Amer. Med. Assoc. 256:3110-3116 (1986). Psoriasis. PA1 Toetterman, T. H. et al., Lancet, 693 (1984). Pure red cell aplasia (PRCA). PA1 Stryckmans, P. A. et al., New Engl. J. Med. 310:655-656 (1984). Aplastic anemia. PA1 Gluckman, Z. etal., Bone Marrow Transplant 3 Suppl. 1, 241 (1988). Aplastic anemia. PA1 Wiener, R. H. et al., Hepatology 7:1025, Abst. #9, (1987). Primary biliary cirrhosis. PA1 Hyams, J. S. et al., Gastroenterology 93:890-893 (1987). Autoimmune hepatitis. PA1 Allison, M. C. et al., Lancet, 902-903 (1984). Crohn's disease. PA1 Brynskor, J. etal., Gastroenterology 92:1330 (1987). Crohn's disease. PA1 Porto, G. B. etal., Ital. J. Gastroenterol. 19:40-41 (1987). Ulcerative colitis. PA1 Appel, S. H. et al., Arch. Neurol. 45:381-386 (1988). ALS. PA1 Tindall, R. S. A. et al., New EnCl. J. Med. 316:719-724 (1987). Myasthenia gravis. Ann. Neurol. 24, No. 1, p. 169,m Abstract P174 (1988). Multiple sclerosis. PA1 Dommasch, D. et al., Neurology 38 Suppl. 2, 28-29 (1988). Multiple sclerosis. PA1 Watzon, A. R. et al., Olin. Nephrol. 25:273-274 (1986). Nephrotic syndrome. PA1 TeJani, A. et al., Kidney Int. 33:729-734 (1988). Nephrotic syndrome. PA1 Meyrier, A. et al., Transplat Proc. 20, Suppl. 4 (Book III), 259-261 (1988). Nephrotic syndrome. PA1 LaGrue, G. et al., Nephron. 44:382-382 (1986). MPGN. PA1 Harper, J. I. et al., Lancet 981-982 (1984). RA PA1 Van Rijthoven, A. W. et al., Ann. Rheum. Dis. 45:726-731 (1986). RA. PA1 Dougados, M. et al., Ann. Rheum. Dis. 47:127-133 (1988) RA. PA1 Stiller, C. R. et al., Science 223: 1362-1367 (1984). IDDM. PA1 Assan, R. et al., Lancet, 67-71 (1985). IDDM. PA1 Bougneres, P. F. et al., New Engl. J. Med. 318:663-670 (1988). IDDM. Diabetes 37:1574-1582 (1988). IDDM.
Many veterinary diseases are also characterized as autoimmune diseases. Autoimmune diseases such as those listed above have been observed in mammals. Papa, F. O. et al., Equine Vet. J. 22:145-146 (1990) infertility of autoimmune origin in the stallion; Gorman, N. T. and L. L. Werner, Brit. Vet. J. 142:403-410, 491-497 and 498-505 (1986) immune mediated diseases of cats and dogs; George, L. W. and S. L. White, Vet. Olin. North Amer. 6:203-213 (1984) autoimmune skin diseases in large mammals; Bennett, D., In. Pract. 6:74-86 (1984) autoimmune diseases in dogs; Halliwell, R. E., J. Amer. vet. Assoc. 181: 1088-1096 ( 1982 ) autoimmune diseases in domesticated animals.
The mechanism by which CsA causes immunosuppression has been established. In vitro, CsA inhibits the release of lymphokines, such as interleukin 2 (IL-2) [Bunjes, D. et al., Eur. J. Immunol. 11:657-661 (1981)] and prevents clonal expansion of helper and cytotoxic T cells [Lareson, E. J. Immunol. 124:2828-2833 (1980)]. CsA has been shown to bind the cytosolic protein, cyclophilin, and inhibit the prolyl-peptidyl cis-trans isomerase (PPIase) activity of that protein. Fischer, G. et al., Nature 337:476-478 (1989); Takahashi, N. etal., Nature 337:473-475 (1989). The PPIases may mediate T cell activation by catalyzing the rotomerization of peptide bonds of prolyl residues.
Recently, a second natural product isolated from Streptomyces, referred to as FK-506, has been demonstrated to be a potent immunosuppresive agent. Tanaka, H. et al., J. Am. Chem. Soc. 109:5031-5033 (1987). FK-506 inhibits IL-2 production, inhibits mixed lymphocyte culture response and inhibits cytotoxic T-cell generation in vitro at 100 times lower concentration than cyclosporin A. Kino, T. etal., J. Antibiot. 15:1256-1265 (1987). FK-506 also inhibits PPIase activity, but is structurally different from CsA and binds to a binding protein (FFaP) distinct from cyclophilin. Harding, M. W. et al., Nature 341:755-760 (1989); Siekierka, J. J., Nature 341:755-757 (1989).